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Vol. 54, Issue 2, 323-374, June 2002
Department of Pharmacology, University of Melbourne, Parkville,
Victoria, Australia (A.C.); and 7TM Pharmacology Systems Research,
Glaxo Smith-Kline Research and Development, Research Triangle Park,
North Carolina (T.K.)
I. Introduction
II. Allosteric Receptor Models of G Protein-Coupled Receptors
A. Historical Perspective
1. Cooperativity in Binding.
2. Allosteric Transitions: Multistate Models of Receptor
Action.
3. Allosteric Interactions: Ternary Complex Models.
B. Behavior of the Ternary Complex Model
C. The Molecular Nature of Allosterism at G Protein-Coupled
Receptors
1. G Protein-Specific Receptor Conformations.
2. Ligand-Specific Receptor Conformations.
III. Detecting Allosteric Interactions
A. Assays of Radioligand Binding
1. Equilibrium Binding Assays.
2. Inhibition Binding Assays.
3. Nonequilibrium (Kinetic) Studies.
B. Assays of Receptor Function
1. Schild Analysis.
2. Additivity of Concentration Ratios.
3. Pharmacological Resultant Analysis.
C. Potential Pitfalls
IV. Usefulness of Allosteric Modulators
V. Location of the Allosteric Site(s)
A. Locks and Keys
B. Modulation by Ions
C. Interactions at the Receptor-G Protein Interface
D. Extracellular Allosteric Sites
1. Multiple Allosteric Sites.
VI. Endogenous Allosteric Modulators
VII. G Protein-Coupled Receptor Complexing
A. Receptor-Receptor Interactions
B. Accessory Proteins
VIII. Conclusions
Acknowledgments
References
G protein-coupled receptors (GPCRs) represent the largest family of cell-surface receptors. These receptors are natural allosteric proteins because agonist-mediated signaling by GPCRs requires a conformational change in the receptor protein transmitted between two topographically distinct binding sites, one for the agonist and another for the G protein. It is now becoming increasingly recognized, however, that the agonist-bound GPCR can also form ternary complexes with other ligands or "accessory" proteins and display altered binding and/or signaling properties in relation to the binary agonist-receptor complex. Allosteric sites on GPCRs represent novel drug targets because allosteric modulators possess a number of theoretical advantages over classic orthosteric ligands, such as a ceiling level to the allosteric effect and a potential for greater GPCR subtype-selectivity. Because of the noncompetitive nature of allosteric phenomena, the detection and quantification of such effects often relies on a combination of equilibrium binding, nonequilibrium kinetic, and functional signaling assays. This review discusses the development and properties of allosteric receptor models for GPCRs and the detection and quantification of allosteric effects. Moreover, we provide an overview of the current knowledge regarding the location of possible allosteric sites on GPCRs and candidate endogenous allosteric modulators. Finally, we discuss the potential for allosteric effects arising from the formation of GPCR oligomers or GPCRs complexed with accessory cellular proteins. It is proposed that the study of allosteric phenomena will become of progressively greater import to the drug discovery process due to the advent of newer and more sensitive GPCR screening technologies.
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B. N. Armbruster and B. L. Roth Mining the Receptorome J. Biol. Chem., February 18, 2005; 280(7): 5129 - 5132. [Full Text] [PDF]
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 C. K. Nielsen, J. I.A. Campbell, J. F. Ohd, M. Morgelin, K. Riesbeck, G. Landberg, and A. Sjolander A Novel Localization of the G-Protein-Coupled CysLT1 Receptor in the Nucleus of Colorectal Adenocarcinoma Cells Cancer Res., February 1, 2005; 65(3): 732 - 742. [Abstract] [Full Text] [PDF]
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L. T. May, Y. Lin, P. M. Sexton, and A. Christopoulos Regulation of M2 Muscarinic Acetylcholine Receptor Expression and Signaling by Prolonged Exposure to Allosteric Modulators J. Pharmacol. Exp. Ther., January 1, 2005; 312(1): 382 - 390. [Abstract] [Full Text] [PDF]
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 L. E. Limbird The Receptor Concept: A Continuing Evolution Mol. Interv., December 1, 2004; 4(6): 326 - 336. [Abstract] [Full Text] [PDF]
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Z. Chen, G. Rogge, C. Hague, D. Alewood, B. Colless, R. J. Lewis, and K. P. Minneman Subtype-selective Noncompetitive or Competitive Inhibition of Human {alpha}1-Adrenergic Receptors by {rho}-TIA J. Biol. Chem., August 20, 2004; 279(34): 35326 - 35333. [Abstract] [Full Text] [PDF]
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R. Bertini, M. Allegretti, C. Bizzarri, A. Moriconi, M. Locati, G. Zampella, M. N. Cervellera, V. Di Cioccio, M. C. Cesta, E. Galliera, et al. Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: Prevention of reperfusion injury PNAS, August 10, 2004; 101(32): 11791 - 11796. [Abstract] [Full Text] [PDF]
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 M. Kindermann, C. Maack, S. Schaller, N. Finkler, K. I. Schmidt, S. Laer, H. Wuttke, H.-J. Schafers, and M. Bohm Carvedilol but Not Metoprolol Reduces {beta}-Adrenergic Responsiveness After Complete Elimination From Plasma In Vivo Circulation, June 29, 2004; 109(25): 3182 - 3190. [Abstract] [Full Text] [PDF]
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 R. S.J. Keast, T. M. Canty, and P. A.S. Breslin The Influence of Sodium Salts on Binary Mixtures of Bitter-tasting Compounds Chem Senses, June 1, 2004; 29(5): 431 - 439. [Abstract] [Full Text] [PDF]
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J. Liu, D. Maurel, S. Etzol, I. Brabet, H. Ansanay, J.-P. Pin, and P. Rondard Molecular Determinants Involved in the Allosteric Control of Agonist Affinity in the GABAB Receptor by the GABAB2 Subunit J. Biol. Chem., April 16, 2004; 279(16): 15824 - 15830. [Abstract] [Full Text] [PDF]
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P. C. Simons, S. M. Biggs, A. Waller, T. Foutz, D. F. Cimino, Q. Guo, R. R. Neubig, W.-J. Tang, E. R. Prossnitz, and L. A. Sklar Real-time Analysis of Ternary Complex on Particles: DIRECT EVIDENCE FOR PARTIAL AGONISM AT THE AGONIST-RECEPTOR-G PROTEIN COMPLEX ASSEMBLY STEP OF SIGNAL TRANSDUCTION J. Biol. Chem., April 2, 2004; 279(14): 13514 - 13521. [Abstract] [Full Text] [PDF]
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A. Lanzafame and A. Christopoulos Investigation of the Interaction of a Putative Allosteric Modulator, N-(2,3-Diphenyl-1,2,4-thiadiazole-5-(2H)-ylidene) Methanamine Hydrobromide (SCH-202676), with M1 Muscarinic Acetylcholine Receptors J. Pharmacol. Exp. Ther., March 1, 2004; 308(3): 830 - 837. [Abstract] [Full Text] [PDF]
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V. Avlani, L. T. May, P. M. Sexton, and A. Christopoulos Application of a Kinetic Model to the Apparently Complex Behavior of Negative and Positive Allosteric Modulators of Muscarinic Acetylcholine Receptors J. Pharmacol. Exp. Ther., March 1, 2004; 308(3): 1062 - 1072. [Abstract] [Full Text] [PDF]
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J. Kniazeff, P.-P. Saintot, C. Goudet, J. Liu, A. Charnet, G. Guillon, and J.-P. Pin Locking the Dimeric GABAB G-Protein-Coupled Receptor in Its Active State J. Neurosci., January 14, 2004; 24(2): 370 - 377. [Abstract] [Full Text] [PDF]
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T. M. Tran, J. Friedman, E. Qunaibi, F. Baameur, R. H. Moore, and R. B. Clark Characterization of Agonist Stimulation of cAMP-Dependent Protein Kinase and G Protein-Coupled Receptor Kinase Phosphorylation of the {beta}2-Adrenergic Receptor Using Phosphoserine-Specific Antibodies Mol. Pharmacol., January 1, 2004; 65(1): 196 - 206. [Abstract] [Full Text] [PDF]
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 R. R. Neubig, M. Spedding, T. Kenakin, and A. Christopoulos International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on Terms and Symbols in Quantitative Pharmacology Pharmacol. Rev., December 1, 2003; 55(4): 597 - 606. [Abstract] [Full Text] [PDF]
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H. Figler, R. A. Olsson, and J. Linden Allosteric Enhancers of A1 Adenosine Receptors Increase Receptor-G Protein Coupling and Counteract Guanine Nucleotide Effects on Agonist Binding Mol. Pharmacol., December 1, 2003; 64(6): 1557 - 1564. [Abstract] [Full Text] [PDF]
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P. C. Simons, M. Shi, T. Foutz, D. F. Cimino, J. Lewis, T. Buranda, W. K. Lim, R. R. Neubig, W. E. McIntire, J. Garrison, et al. Ligand-Receptor-G-Protein Molecular Assemblies on Beads for Mechanistic Studies and Screening by Flow Cytometry Mol. Pharmacol., November 1, 2003; 64(5): 1227 - 1238. [Abstract] [Full Text] [PDF]
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H. Schaffhauser, B. A. Rowe, S. Morales, L. E. Chavez-Noriega, R. Yin, C. Jachec, S. P. Rao, G. Bain, A. B. Pinkerton, J.-M. Vernier, et al. Pharmacological Characterization and Identification of Amino Acids Involved in the Positive Modulation of Metabotropic Glutamate Receptor Subtype 2 Mol. Pharmacol., October 1, 2003; 64(4): 798 - 810. [Abstract] [Full Text] [PDF]
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S. Urwyler, M. F. Pozza, K. Lingenhoehl, J. Mosbacher, C. Lampert, W. Froestl, M. Koller, and K. Kaupmann N,N'-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) and Structurally Related Compounds: Novel Allosteric Enhancers of {gamma}-Aminobutyric AcidB Receptor Function J. Pharmacol. Exp. Ther., October 1, 2003; 307(1): 322 - 330. [Abstract] [Full Text] [PDF]
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 K. Biber, M. W. Zuurman, H. Homan, and H. W. G. M. Boddeke Expression of L-CCR in HEK 293 cells reveals functional responses to CCL2, CCL5, CCL7, and CCL8 J. Leukoc. Biol., August 1, 2003; 74(2): 243 - 251. [Abstract] [Full Text] [PDF]
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U. Voigtlander, K. Johren, M. Mohr, A. Raasch, C. Trankle, S. Buller, J. Ellis, H.-D. Holtje, and K. Mohr Allosteric Site on Muscarinic Acetylcholine Receptors: Identification of Two Amino Acids in the Muscarinic M2 Receptor That Account Entirely for the M2/M5 Subtype Selectivities of Some Structurally Diverse Allosteric Ligands in N-Methylscopolamine-Occupied Receptors Mol. Pharmacol., July 1, 2003; 64(1): 21 - 31. [Abstract] [Full Text] [PDF]
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C. Trankle, O. Weyand, U. Voigtlander, A. Mynett, S. Lazareno, N. J. M. Birdsall, and K. Mohr Interactions of Orthosteric and Allosteric Ligands with [3H]Dimethyl-W84 at the Common Allosteric Site of Muscarinic M2 Receptors Mol. Pharmacol., July 1, 2003; 64(1): 180 - 190. [Abstract] [Full Text] [PDF]
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Z.-G. Gao, S.-K. Kim, A. S. Gross, A. Chen, J. B. Blaustein, and K. A. Jacobson Identification of Essential Residues Involved in the Allosteric Modulation of the Human A3 Adenosine Receptor Mol. Pharmacol., May 1, 2003; 63(5): 1021 - 1031. [Abstract] [Full Text] [PDF]
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A. Benians, J. L. Leaney, G. Milligan, and A. Tinker The Dynamics of Formation and Action of the Ternary Complex Revealed in Living Cells Using a G-protein-gated K+ Channel as a Biosensor J. Biol. Chem., March 14, 2003; 278(12): 10851 - 10858. [Abstract] [Full Text] [PDF]
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A. Sachpatzidis, B. K. Benton, J. P. Manfredi, H. Wang, A. Hamilton, H. G. Dohlman, and E. Lolis Identification of Allosteric Peptide Agonists of CXCR4 J. Biol. Chem., January 3, 2003; 278(2): 896 - 907. [Abstract] [Full Text] [PDF]
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S. Lazareno, A. Popham, and N. J. M. Birdsall Analogs of WIN 62,577 Define a Second Allosteric Site on Muscarinic Receptors Mol. Pharmacol., December 1, 2002; 62(6): 1492 - 1505. [Abstract] [Full Text] [PDF]
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 J. K. Chen, J. Taipale, M. K. Cooper, and P. A. Beachy Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened Genes & Dev., November 1, 2002; 16(21): 2743 - 2748. [Abstract] [Full Text] [PDF]
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J. K. Chen, J. Taipale, K. E. Young, T. Maiti, and P. A. Beachy Small molecule modulation of Smoothened activity PNAS, October 29, 2002; 99(22): 14071 - 14076. [Abstract] [Full Text] [PDF]
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